John J. Mariani

Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial

Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double-blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow back method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P=.02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P=.02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.

Treatment Strategies for Co‐Occurring ADHD and Substance Use Disorders

Attention-deficit hyperactivity disorder (ADHD) is a common co-occurring mental disorder among patients with substance use disorders (SUD). Clinicians must be cognizant of the complicated nature of diagnosis and treatment of ADHD when comorbid with SUD. Pharmacotherapy remains the mainstay of treatment for ADHD, although complementary psychotherapeutic approaches have been developed. Psychostimulant medications are the most commonly used medications to treat ADHD, but many clinicians are reluctant to prescribe stimulants to patients with SUD. Recommendations for treatment planning and clinical management for patients with co-occurring ADHD and SUD are discussed.

Quantification and Comparison of Marijuana Smoking Practices: Blunts, Joints, and Pipes

The quantification method for collecting self-reported marijuana use data is not standardized as it is for alcohol or cigarettes, which presents a methodologic challenge for marijuana use disorder treatment studies. Serum and urine markers of marijuana use have a long half-life, limiting their utility as a clinical trial outcome measure. Structured calendar-based interview procedures can accurately measure the frequency of self-reported marijuana use, but are unable to reliably address issues such as quantity of use or potency. This study compared the quantity and assigned-dollar value among users of blunts, joints, and pipes enrolled in two clinical trials testing pharmacotherapies for marijuana dependence. The timeline follow-back method was modified to incorporate using a surrogate substance to represent marijuana to enable participants to estimate the amount and value used. Blunt users were mostly black and Hispanic, while users of joints and pipes were primarily white. Participants reported that they placed 50% more marijuana in blunts than in joints and placed more than twice the amount of marijuana in blunts than in pipes. These findings demonstrate the feasibility of using a surrogate weight estimation procedure to augment calendar-based methods of measuring self-reported marijuana use. Individual variability in use practices limits the utility of this method to estimating within-subject comparisons, rather than between subject comparisons.

A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal.

Gabapentin was compared with phenobarbital for the treatment of alcohol withdrawal in a randomized, open-label, controlled trial in 27 inpatients. There were no significant differences in the proportion of treatment completers between treatment groups or the proportion of patients in each group requiring rescue medication for breakthrough signs and symptoms of alcohol withdrawal. There were no significant treatment differences in withdrawal symptoms or psychological distress, nor were there serious adverse events. These findings suggest that gabapentin may be as effective as phenobarbital in the treatment of alcohol withdrawal. Given gabapentins favorable pharmacokinetic profile, further study of its effectiveness in treating alcohol withdrawal is warranted.

Psychostimulant Treatment of Cocaine Dependence

The use of stimulant medications for the treatment of cocaine dependence is an evolving scientific line of research. To date, the most promising results are with the higher-potency medications, the amphetamine analogues, or a combination of a dopaminergic medication with a contingency management behavioral intervention. The development of effective pharmacotherapies for opioid and nicotine dependence using an agonist replacement approach suggests that these promising findings needs to continue to be vigorously investigated. In clinical trial reports, there are very few instances of cardiovascular adverse events, which suggests that for well-selected patients with cocaine dependence, stimulant replacement therapy can be safe. However, clinical trial eligibility criteria excludes most high-risk patients from participating, and introducing stimulant substitution to the wider treatment community would likely expose more vulnerable patients to the medical risks associated with stimulant treatment while using cocaine. As treatment development research moves forward, attention must be paid to helping clinicians select patients who are most likely to benefit from stimulant substitution treatment and how to identify those at risk. An additional concern with the use of stimulant medication treatment of cocaine dependence is prescribing controlled substances for patients with active substance use disorders. Again, within a clinical trial, medication supplies are monitored and distributed carefully in small quantities. In a community setting, misuse or diversion will be risks associated with prescribing controlled substances to patients with addictive disorders, but therapeutic strategies for monitoring and limiting that risk can be implemented. Psychostimulant pharmacotherapy is a promising line of research for the treatment of cocaine dependence, a condition for which no effective pharmacotherapy has been identified. Further research is required to confirm positive results from single-site trials, in particular the study of amphetamines as a treatment for cocaine dependence. As this literature evolves, strategies to manage the risk of prescribing controlled substances to patients with addictive disorders need to be tested and refined. Biases against using controlled substances as a treatment for cocaine dependence should be challenged, much in the way the use of agonist treatment transformed the treatment of opioid dependence despite initial resistance from the field.

Extended-release mixed amphetamine salts and topiramate for cocaine dependence: a randomized controlled trial.

BACKGROUND Cocaine dependence is a substantial public health problem, yet there are no clearly effective medication treatments. Amphetamine and topiramate have both shown promise for the treatment of cocaine dependence in preclinical and early-stage clinical studies. METHODS Eighty-one cocaine-dependent adults were randomized to receive a combination of extended-release mixed amphetamine salts (MAS-ER) and topiramate or placebo for 12 weeks under double-blind conditions. MAS-ER doses were titrated over 2 weeks to a maximum dose of 60 mg daily, and topiramate doses were titrated over 6 weeks to a maximum dose of 150 mg twice daily. All participants received a supportive behavioral intervention. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence as measured by urine toxicology confirmed self-report. RESULTS The overall proportion of participants who achieved 3 consecutive weeks of abstinence was larger in the extended-release mixed amphetamine salts and topiramate group (33.3%) than in placebo group (16.7%). There was a significant moderating effect of baseline total number of cocaine use days (Wald χ(2) = 3.75, df = 1, p = .05) on outcome, suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use. CONCLUSIONS The results of this study supported our hypothesis that the combination of MAS-ER and topiramate would be superior to placebo in achieving 3 weeks of consecutive abstinence. These findings provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals.

Vaccine for cocaine dependence: A randomized double-blind placebo-controlled efficacy trial

AIMS We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence. METHODS This 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome. RESULTS The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of ≥42 μg/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths. CONCLUSIONS The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.

Extended-release mixed amphetamine salts vs placebo for comorbid adult attention-deficit/hyperactivity disorder and cocaine use disorder a randomized clinical trial

IMPORTANCE Adult attention-deficit/hyperactivity disorder (ADHD) is prevalent but often unrecognized, in part because it tends to co-occur with other disorders such as substance use disorders. Cocaine use disorder is one such disorder with high co-occurrence of ADHD. OBJECTIVE To examine whether treatment of co-occurring ADHD and cocaine use disorder with extended-release mixed amphetamine salts is effective at both improving ADHD symptoms and reducing cocaine use. DESIGN, SETTING, AND PARTICIPANTS Thirteen-week, randomized, double-blind, 3-arm, placebo-controlled trial of participants meeting DSM-IV-TR criteria for both ADHD and cocaine use disorder conducted between December 1, 2007, and April 15, 2013, at 2 academic health center substance abuse treatment research sites. One hundred twenty-six adults diagnosed as having comorbid ADHD and cocaine use disorder were randomized to extended-release mixed amphetamine salts or placebo. Analysis was by intent-to-treat population. INTERVENTIONS Participants received extended-release mixed amphetamine salts (60 or 80 mg) or placebo daily for 13 weeks and participated in weekly individual cognitive behavioral therapy. MAIN OUTCOMES AND MEASURES For ADHD, percentage of participants achieving at least a 30% reduction in ADHD symptom severity, measured by the Adult ADHD Investigator Symptom Rating Scale; for cocaine use, cocaine-negative weeks (by self-report of no cocaine use and weekly benzoylecgonine urine screens) during maintenance medication (weeks 2-13) and percentage of participants achieving abstinence for the last 3 weeks. RESULTS More patients achieved at least a 30% reduction in ADHD symptom severity in the medication groups (60 mg: 30 of 40 participants [75.0%]; odds ratio [OR] = 5.23; 95% CI, 1.98-13.85; P < .001; and 80 mg: 25 of 43 participants [58.1%]; OR = 2.27; 95% CI, 0.94-5.49; P = .07) compared with placebo (17 of 43 participants [39.5%]). The odds of a cocaine-negative week were higher in the 80-mg group (OR = 5.46; 95% CI, 2.25-13.27; P < .001) and 60-mg group (OR = 2.92; 95% CI, 1.15-7.42; P = .02) compared with placebo. Rates of continuous abstinence in the last 3 weeks were greater for the medication groups than the placebo group: 30.2% for the 80-mg group (OR = 11.87; 95% CI, 2.25-62.62; P = .004) and 17.5% for the 60-mg group (OR = 5.85; 95% CI, 1.04-33.04; P = .04) vs 7.0% for placebo. CONCLUSIONS AND RELEVANCE Extended-release mixed amphetamine salts in robust doses along with cognitive behavioral therapy are effective for treatment of co-occurring ADHD and cocaine use disorder, both improving ADHD symptoms and reducing cocaine use. The data suggest the importance of screening and treatment of ADHD in adults presenting with cocaine use disorder. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00553319.

A randomized double-blind, placebo-controlled trial of venlafaxine-extended release for co-occurring cannabis dependence and depressive disorders.

AIM To evaluate whether venlafaxine-extended release (VEN-XR) is an effective treatment for cannabis dependence with concurrent depressive disorders. DESIGN This was a randomized, 12-week, double-blind, placebo-controlled trial of out-patients (n = 103) with DSM-IV cannabis dependence and major depressive disorder or dysthymia. Participants received up to 375 mg VEN-XR on a fixed-flexible schedule or placebo. All patients received weekly individual cognitive-behavioral psychotherapy that primarily targeted marijuana use. SETTINGS The trial was conducted at two university research centers in the United States. PARTICIPANTS One hundred and three cannabis-dependent adults participated in the trial. MEASUREMENTS The primary outcome measures were (i) abstinence from marijuana defined as at least two consecutive urine-confirmed abstinent weeks and (ii) improvement in depressive symptoms based on the Hamilton Depression Rating Scale. FINDINGS The proportion of patients achieving a clinically significant mood improvement (50% decrease in Hamilton Depression score from baseline) was high and did not differ between groups receiving VEN-XR (63%) and placebo (69%) (χ1 (2)  = 0.48, P = 0.49). The proportion of patients achieving abstinence was low overall, but was significantly worse on VEN-XR (11.8%) compared to placebo (36.5%) (χ1 (2)  = 7.46, P < 0.01; odds ratio = 4.51, 95% confidence interval: 1.53, 13.3). Mood improvement was associated with reduction in marijuana use in the placebo group (F1,179  = 30.49, P < 0.01), but not the VEN-XR group (F1,186  = 0.02, P = 0.89). CONCLUSIONS For depressed, cannabis-dependent patients, venlafaxine-extended release does not appear to be effective at reducing depression and may lead to an increase in cannabis use.

Atomoxetine Treatment for Cocaine Abuse and Adult Attention Deficit/Hyperactivity Disorder (ADHD): A Preliminary Open Trial

The purpose of this 12-week open-label trial was to evaluate the potential utility of atomoxetine for the treatment of attention deficit/hyperactivity disorder (ADHD) in cocaine-dependent treatment seekers. The sample consisted of 20 participants who met DSM-IV-TR criteria for ADHD and cocaine dependence. Using several measures to assess ADHD, there was a significant reduction in ADHD symptoms. There was no significant decrease in cocaine use throughout the trial. Taken together, although cocaine-dependent individuals showed some reduction in ADHD symptoms while receiving atomoxetine, the high dropout rate and lack of impact on cocaine use may limit its utility in adults with ADHD who are currently abusing cocaine.